DESCRIPTION (taken from the application) Candidate: Dr. John Mickle earned his Ph.D. through the Cell and Molecular Biology Program at Boston University and simultaneously received comprehensive training in human molecular genetics at the Center for Human Genetics, Boston University School of Medicine. He has been a very productive post-doctoral fellow in the laboratory of Dr. Garry Cutting at Johns Hopkins School of Medicine for the past four years. Dr. Mickle has taken an interdisciplinary approach to study the consequence of disease-associated mutations upon the chloride channel (CFTR) that is defective in the inherited disease cystic fibrosis (CF). Dr. Mickle worked in the laboratory of Dr. William Guggino in the Department of Physiology at Hopkins to become proficient in electrophysiology. Dr. Mickle's research has focused on the interaction between CFTR and outwardly rectified chloride channels in the same cell, and he has investigated this interaction by evaluating the function of disease-associated mutations and divergent forms of CFTR. Dr. Mickle is a member of the Mount Desert Island Biological Laboratory and has established collaborations with Dr. Karl Karnaky Jr. of the Medical University of South Carolina and Dr. Jack Riordan of the Mayo Clinic in Scottsdale, Arizona. Pursuit of an individual research project is the appropriate next phase for Dr. Mickle in his development as a successful independent investigator. Emphasis will be placed on manuscript writing, research talks, and teaching in preparation for independence. Environment: Dr. Cutting's laboratory is well-equipped for both molecular biology and electrophysiology, ample research space is available for Dr. Mickle to perform his research project. A confocal laser microscope facility is available in an adjacent building, and additional expertise in electrophysiology is available from the laboratories of Dr. Bill Guggino and other principle investigators in the Cystic Fibrosis research group at Hopkins. Research: Life-limiting pulmonary disease is a hallmark of the common genetic disorder cystic fibrosis (CF). The disorder is caused by dysfunction of the CF transmembrane conductance regulator (CFTR). In airway epithelial cells CFTR is both a chloride channel and a regulator of several different ion channels. Both functions implicate CFTR as a key component in the coordination of ion movement across apical membranes of airway cells. Thus, pulmonary disease may be influenced by mutations in CFTR that effect the channel and/or regulatory function. Proteins involved in the regulatory pathways also may influence lung function independent of CFTR. The overall goal of the proposed research is to explore to relationship between CFTR, its regulation of separate channels and phenotype. This research will increase our understanding of CF pathophysiology, elucidate intra- and intermolecular interactions of therapeutic significance, and alter diagnostic criteria for CF and related disorders.